2,3-trans-disubstituted tropane compounds which have useful pharmaceutical utility

ABSTRACT

The present invention discloses compounds of the formula ##STR1## any mixture thereof, or a pharmaceutically acceptable salt thereof; wherein R, R 3 , and R 4  each have the meanings set forth in the specification. 
     The compounds possess valuable pharmaceutical properties as dopamine reuptake inhibitors.

The present invention relates to: novel tropane derivatives which havepronounced anti drug abuse, antidepressant and anti-Parkinsonianactivity and, at the same time, a low degree of undesired side effects;methods for the preparation of the novel tropane derivatives;pharmaceutical compositions containing the novel tropane derivatives;and methods for the treatment of drug abuse, depression andParkinsonism, by administering a therapeutically effective amount of oneor more of the novel tropane derivatives to a living animal body,including a human.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide novel tropanederivatives having anti drug abuse, antidepressant and anti-Parkinsonianactivity.

Another object of the invention is to provide novel pharmaceuticalcompositions containing the novel tropane derivatives which are usefulfor the treatment of drug abuse, depression and Parkinsonism.

Still another object of the invention is to provide a method of treatingdrug abuse, depression and Parkinsonism by administering atherapeutically effective amount of one or more of the novel tropanederivatives to a living animal body, including a human.

Other objects will become apparent hereinafter to one skilled in theart.

BACKGROUND OF THE INVENTION

It is well known, that cocaine has a variety of pharmacological actions,primarily a strong CNS stimulation and local anesthetic action. Theseeffects are accompanied by high toxicity and dependence liability. (seefor example R. L. Clarke et al in Journal of Medicinal Chemistry 16(11),1261-1267 (1973). The dependence liability is thought to be related to acombination of cocaine's powerful stimulant activity, short term ofaction, and rapid onset of action together with its strongdopamine-releasing properties. Further it is well known, that cocainealso possess powerful dopamine reuptake inhibiting activity. It isbelieved, that compounds having long lasting selective dopaminereuptake-inhibiting properties, and being devoid of dopamine releasingproperties, will be extremely useful as a novel type of antidepressantand anti-Parkinsonian agent. Furthermore such compounds will beextremely useful in the treatment of drug addiction, and especially inthe treatment of cocaine addiction or misuse.

During the years many attempts have been made to optimize upon theproperties of cocaine. Many derivatives of cocaine and of its isomershave been synthesized. See for example R. L. Clarke et al in Journal ofMedicinal Chemistry 16(11), 1261-1267 (1973) and F. Ivy Caroll et al inJournal of Medicinal Chemistry 34, 883-886 (1991 ). Many of thesederivatives and probably most pronounced the derivatives of R. L. Clarkeet al above are very powerful stimulant compounds and have been found tobe very potent dopamine reuptake inhibitors. However none of the cocainederivatives synthesized until today have been found to be devoid ofundesired side effects. R. L. Clarke et al in above paper notes at page1265, that an enantiomer (trans isomer) of a closely related compound(cis isomer as is cocaine) was not stimulant, and at the same page, thatmoving a 2-carboxy function from an axial (cis isomer) to an equatorialconfiguration (trans isomer) gave a compound which was inactive in theiocomotor screen (>256 mg/kg), but appeared to produce a slightstimulation. P. C. Meltzer et al in Journal of Medicinal Chemistry,36(7), 855-862 (1993) notes that the trans isomers are biologicallyinactive.

Throughout the literature all efforts of derivating cocaine have focusedupon optimizing the dopamine reuptake inhibiting properties and ligandaffinity by synthesizing further cis isomers (just as cocaine),undoubtedly because these compounds have been found to be the mostpotent dopamine reuptake inhibitors as well as the most potent ligandsin various binding assays. This also includes the findings published byF. Ivy Carroll et al in J. Chem. Soc. Chem. Commun. pp. 44-46 (1993).

THE PRESENT INVENTION

The inventors to the present invention became scientifically interestedin the compounds of R. L. Clarke et al and decided to synthesize thecompound designated No. 13 by Clarke et al (Win 35,428). During thesyntheses of Win 35,428, the trans isomer of Win 35,428 was isolated asa side product by the present inventors. During a carefulcharacterization of both of these epimeric compounds it was surprisinglynoted, that the trans isomer, though being only close to 50 times lesspotent as compared to the cis isomer (Win 35,428) as a dopamine reuptakeinhibitor, then in contrast to Win 35,428, at every relevant dosinglevel tested appeared essentially or totally devoid of side effects asmeasured by excitatory Iocomotor activity and rearing responses as wellas by abnormal stereotyped behaviour, and as well as the fact that thecompound was essentially free of dopamine releasing properties, all instrong contrast to Win 35,428 and cocaine.

These new and surprising findings prompted the inventors of the presentinvention to synthesize a large series of derivatives of Win 35,428, itsisomers and furthermore more remotely related compounds.

It was thereby surprisingly found that, by selecting the trans isomer,rather than the cis isomer as appearing throughout the literature, andby substituting the CO₂ Me group of Win 35,428 for various othersubstituents and most pronounced for various sterically largesubstituents, it became possible at one and the same time, to maintainand enhance the dopamine reuptake inhibiting properties of thecompounds, as well as to further reduce or eliminate the side effects inthe form of excitatory Iocomotor activity and rearing responses as wellas by way of abnormal stereotyped behaviour. Further it was found thatthe compounds were devoid of dopamine releasing properties. Mostsurprisingly a strong and potent anti-Parkinsonian and antidepressantactivity remained with the compounds. Certain of the compounds providedherewith also possess very potent serotonine (5-hydroxythryptamine,5-HT) reuptake inhibiting activity in combination with their potentdopamine reuptake inhibiting activity, While it is well established thateither selective dopamine reuptake inhibitors or selective serotoninereuptake inhibitors are efficient antidepressive agents, then it is veryoften necessary to use unselective dopamine/serotonine uptake inhibitorycompounds, such as imipramine and amitriptyline, to stabilize mood inseverely depressed patients. Therefore compounds of the inventionexhibiting this combination of activity may also be effective in moodstabilization of such severely depressed patients. An example of such acompound is (1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(4-fluorophenyl)tropane.

The invention then, inter alia, comprises the following, alone or incombination:

A method of treating a disorder or disease of a living animal body,including a human, which disorder or disease is responsive to theinhibition of dopamine reuptake, comprising the step of administering tosuch a living animal body, including a human, in need thereof aneffective amount of a compound having the formula ##STR2## any mixturethereof, or a pharmaceutically acceptable salt thereof; wherein

R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkyl or2-hydroxyethyl;

R³ is

(CH₂)_(n) CO₂ R¹¹ ;

COR¹¹ ;

CH₂ R¹² ;

wherein R¹¹ is alkyl; cycloalkyl; cycloalkylalkyl; phenyl which may besubstituted one or more times with substituents selected from the groupconsisting of halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino,nitro, or aryl; phenylphenyl; pyridyl which may be substituted one ormore times with substituents selected from the group consisting ofhalogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, oraryl; thienyl which may be substituted one or more times withsubstituents selected from the group consisting of halogen, CF₃, CN,alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, or aryl; or benzyl; n is0 or 1; and R¹² is O-phenyl which may be substituted one or more timeswith substituents selected from the group consisting of halogen, CF₃,CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, or aryl; orO-CO-phenyl which may be substituted one or more times with substituentsselected from the group consisting of halogen, CF₃, CN, alkoxy, alkyl,alkenyl, alkynyl, amino, nitro, or aryl; and

R⁴ is

phenyl which may be substituted one or more times with substituentsselected from the group consisting of halogen, CF₃, CN, alkoxy, alkyl,alkenyl, alkynyl, amino, nitro, or aryl;

3,4-methylenedioxyphenyl;

benzyl which may be substituted one or more times with substituentsselected from the group consisting of halogen, CF₃, CN, alkoxy, alkyl,alkenyl, alkynyl, amino, nitro, or aryl;

aryl which may be substituted one or more times with substituentsselected from the group consisting of halogen, CF₃, CN, alkoxy, alkyl,alkenyl, alkynyl, amino, nitro, or aryl; or

naphthyl which may be substituted one or more times with substituentsselected from the group consisting of halogen, CF₃, CN, alkoxy, alkyl,alkenyl, alkynyl, amino, nitro, or aryl; and

a method as above, wherein depression or Parkinsonism is treated; and

a method as above wherein drug addiction and/or abuse is treated; and

a method as above wherein cocaine and/or amphetamine addiction and/orabuse is treated; and

the method as first above, wherein the compound employed is(1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(4-fluorophenyl)tropane; or apharmaceutically-acceptable addition salt thereof; and

the method as first above, wherein the active ingredient is administeredin the form of a pharmaceutical composition thereof, in which it ispresent together with at least one pharmaceutically-acceptable carrieror diluent; and furthermore

a compound having the formula ##STR3## any mixture thereof, or apharmaceutically acceptable salt thereof; wherein

R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkyl or2-hydroxyethyl;

R³ is

(CH₂)_(n) CO₂ R¹¹ ;

CH₂ R¹² ;

wherein R¹¹ is alkyl; cycloalkyl; cycloalkylalkyl; phenyl which may besubstituted one or more times with substituents selected from the groupconsisting of halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino,nitro, or aryl; phenylphenyl; pyridyl which may be substituted one ormore times with substituents selected from the group consisting ofhalogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, oraryl; thienyl which may be substituted one or more times withsubstituents selected from the group consisting of halogen, CF₃, CN,alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, or aryl; or benzyl; n is1; and R¹² is O-phenyl which may be substituted one or more times withsubstituents selected from the group consisting of halogen, CF₃, CN,alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, or aryl; or O--CO-phenylwhich may be substituted one or more times with substituents selectedfrom the group consisting of halogen, CF₃, CN, alkoxy, alkyl, alkenyl,alkynyl, amino, nitro, or aryl; and

R⁴ is

phenyl which may be substituted one or more times with substituentsselected from the group consisting of halogen, CF₃, CN, alkoxy, alkyl,alkenyl, alkynyl, amino, nitro, or aryl;

3,4-methylenedioxyphenyl;

benzyl which may be substituted one or more times with substituentsselected from the group consisting of halogen, CF₃, CN, alkoxy, alkyl,alkenyl, alkynyl, amino, nitro, or aryl;

aryl which may be substituted one or more times with substituentsselected from the group consisting of halogen, CF₃, CN, alkoxy, alkyl,alkenyl, alkynyl, amino, nitro, or aryl; or

naphthyl which may be substituted one or more times with substituentsselected from the group consisting of halogen, CF₃, CN, alkoxy, alkyl,alkenyl, alkynyl, amino, nitro, or aryl;

and a compound as above which is(1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(4-fluorophenyl)tropane; or apharmaceutically-acceptable addition salt thereof; and

a pharmaceutical composition, comprising an effective amount of acompound as above, or a pharmaceutically-acceptable addition saltthereof, together with at least one pharmaceutically-acceptable carrieror diluent; and

the use of a compound as any above for the manufacture of a medicamentfor the treatment of a disorder or disease of a living animal body,including a human, which disorder or disease is responsive to theinhibition of dopamine reuptake in the central nervous system.

Examples of pharmaceutically-acceptable addition salts include inorganicand organic acid addition salts such as the hydrochloride, hydrobromide,phosphate, nitrate, perchlorate, sulphate, citrate, lactate, tartrate,maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate,benzenesulfonate, methanesulfonate, stearate, succinate, glutamate,glycollate, toluene-p-sulphonate, formate, malonate,naphthalene-2-sulphonate, salicylate and the acetate. Such salts areformed by procedures well known in the art.

Other acids such as oxalic acid, while not in themselvespharmaceutically acceptable may be useful in the preparation of saltsuseful as intermediates in obtaining compounds of the invention andtheir pharmaceutically acceptable acid addition salts.

Halogen is fluorine, chlorine, bromine, or iodine; chlorine and bromineare preferred.

Alkyl means a straight chain or branched chain of one to six carbonatoms or cyclic alkyl of from three to seven carbon atoms, including butnot limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl; methyl, ethyl, propyl and isopropyl are preferred groups.

Alkenyl means a group of two to six carbon atoms, including one doublebond, for example, but not limited to ethylene, 1,2- or 2,3-propylene,1,2-, 2,3-, or 3,4-butylene.

Alkynyl means a group of two to six carbon atoms, including one triplebond, for example, but not limited to ethynyl, 2,3-propynyl, 2,3- or3,4-butynyl.

Cycloalkyl means cycloalkyl of three to seven carbon atoms.

Cycloalkylalkyl means cycloalkyl as above and alkyl as above, meaningfor example, cyclopropylmethyl.

Alkoxy is O-alkyl, wherein alkyl is as defined above.

Amino is NH₂ or NH-alkyl or N-(alkyl)₂, wherein alkyl is as definedabove.

Aryl is a 5- or 6-membered heterocyclic monocyclic group. Such an arylgroup includes, for example, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl,1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl,3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl.

I.p. means intraperetoneally, which is a well known route ofadministration.

P.o. means peroral, which is a well known route of administration.

Further, the compounds of this invention may exist in unsolvated as wellas in solvated forms with pharmaceutically acceptable solvents such aswater, ethanol and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thisinvention.

It will be appreciated by those skilled in the art that some of thecompounds of the present invention contain at least one chiral centreand that such compounds exist in the form of a pair of optical isomers(i.e. enantiomers). The invention includes all such isomers and mixturesthereof including racemic mixtures.

Some of the compounds of the present invention exist in (+) and (-)forms as well as in racetalc forms. Racetalc forms can be resolved intothe optical antipodes by known methods, for example, by separation ofdiastereomeric salts thereof with an optically active acid, andliberating the optically active amine compound by treatment with a base.Another method for resolving racemates into the optical antipodes isbased upon chromatography on an optically active matrix. Racetalccompounds of the present invention can thus be resolved into theiroptical antipodes, e.g., by fractional crystallization of d- orl-(tartrates, mandelates, or camphorsulphonate) salts for example. Thecompounds of the present invention may also be resolved by the formationof diastereomeric amides by reaction of the compounds of the presentinvention with an optically active activated carboxylic acid such asthat derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine,(+) or (-) camphanic acid or by the formation of diastereomericcarbamates by reaction of the compounds of the present invention with anoptically active chloroformate or the like.

Additional methods for the resolvation of optical isomers, known tothose skilled in the art may be used, and will be apparent to theaverage worker skilled in the art. Such methods include those discussedby J. Jaques, A. Collet, and S. Wilen in "Enantiomers, Racemates, andResolutions", John Wiley and Sons, New York (1981).

Starting materials for the processes described in the presentapplication are known or can be prepared by known processes fromcommercially available chemicals.

The products of the reactions described herein are isolated byconventional means such as extraction, crystallization, distillation,chromatography, and the like.

The compounds of the invention and their pharmaceutically acceptablederivatives may be prepared by any method known in the art for thepreparation of compounds of the invention and compounds of analogousstructure, as shown in the representative examples which follow.

Biology

The compounds of the present invention are potent dopamine reuptakeinhibitors.

The compounds of the present invention have been tested for theirability to inhibit reuptake of dopamine in synaptosomes of rat forebmin.

Test procedure

Fresh whole forebmin (at 0°-4° C.) from male Wistar rats (150-200 g) ishomogenized in a glass homogenizer with a teflon pestle in 20×volumes0.32M sucrose. The homogenate is centrifuged at 1000×g (˜2900 rpm) for10 min. The pellet is discarded and the supernatant is used for uptakeassays.

A Krebs Buffer (119 mM NaCI, 24 mM NaHCO₃, 2.1 mM KCl, 1.2 mM KH₂ PO₄,1.8 mM CaCl₂, 2 mM MgSO₄, 7H₂ O, 12 mM glucose) is equilibrated with anatmosphere of 96% O₂ : 4% CO₂, for at least 60 min at 37° C. To 5 mlKrebs-buffer 100 μl of the radioactivity is added (3H-dopamine 1×10⁻⁹ Mfinal concentration) and 100 μl test substance solution and 200 μl oftissue suspension. The samples are thoroughly mixed and incubated 10 minat 37° C. followed by 2 min at 0° C. After incubation the samples arepoured directly onto Whatman GF/C glass fibre filters under suction andimmediately washed with 2×5 ml ice-cold 0.9% saline (NaCI) buffer. Tothe filter is added 3 ml of scintillation fluid, and the amount ofradioactivity on the filters is determined by conventional liquidscintillation counting. The test value is given as the IC₅₀ (theconcentration (μM) Of the test substance which inhibits the uptake by50%). Test results obtained by testing selected compounds of the presentinvention will appear from the below table:

                  TABLE                                                           ______________________________________                                                             Dopamine reuptake                                        Compound             inhibiting activity                                      ______________________________________                                        (1R,2R,3S)-2-(4-Chlorophenoxy-                                                                      0.39 μM                                              methyl)-3-(4-fluorophenyl)tropane                                             (1R,2R,3S)-2-carbomethoxy-                                                                          0.10 μM                                              3-(2-naphthyl)-tropane                                                        (1R,2R,3S)-2-carbomethoxy-                                                                         0.016 μM                                              3-(3,4-dichlorophenyl)-tropane                                                ______________________________________                                    

The compounds of the present invention have been tested for theirantiparkinsonian activity by their ability to antagonizehaloperidol-induced catalepsy. This model is recognized in the art as avery reliable model for antiparkinsonian activity.

The Catalepsy test for antiparkinsonian effects.

The principle behind the haloperidol catalepsy test relates to the factthat the drug haloperidol (Serenase®) induces a receptor blockade ofpost synaptic dopamine receptors within the dopamine innervated corpusstriatum of the rat brain. Following the blockade of active dopamineneurotransmission of the striatum a state of rigid immobility isinduced, during which the rat can be placed in various totally abnormalimmobile postures involving the forelegs and the whole body. Theseimmobile postures can also be produced by high doses of haloperidol toseveral other animal species(mice, dog) as well as primates, includinghumans. The immobile posture effect induced by haloperidol closelyresembles the state of Parkinson's disease in humans, which is due to adeficit of the dopaminergic innervation of the striatal complex (nucleuscaudatus, putamen).

The day before testing, the rats weighing 200-250 g are housed 2 and 2together in standard macrolon cages.

The test substance is usually given perorally 1 h before a standard doseof the dopamine antagonist haloperidol 0.25 mg/kg given subcutaneously.The testing for the immobile catalepsy syndrome includes 4 testsperformed in the following consecutive order:

1 ) a vertical wire netting (40×40 cm high). The meshes (openings) ofthe nettings are approximately 1×2 cm.

2) a horizontal bar 9 cm above the floor

3) a 9 cm high block (bar)

4) a 3 cm high block (cork)

The rats were scored for the immobile cataleptic syndrome every 15 minin all 4 tests starting 15 min after the haloperidol injection.

The intensity of catalepsy was tested during 10 sec in all tests andevaluated according to a criteria of 10 sec of total immobility for ascore of 2. Minor movements of the head or the body give the score of 1and a score of 0 is given if the rat shows no symptoms.

The rat was placed in the middle of the vertical wire netting, then onthe horizontal bar in an extended position with support by both theforelegs on the bar.

The rats were then tested, whether or not they were willing to sit withthe left or right forelegs placed first on the 9 and then on the 3 cmblock for a duration of 10 sec. The maximum score for all 4 tests isthus a total of 8.

                  TABLE                                                           ______________________________________                                                            Minimum effective dose                                    Compound            (peroral administration)                                  ______________________________________                                        (1R,2R,3S)-2-(4-Chlorophenoxy-                                                                       <1     mg/kg                                           methyl)-3-(4-fluorophenyl)tropane                                             (1R,2R,3S)-2-carbomethoxy-                                                                           1.0    mg/kg                                           3-(2-naphthyl)-tropane                                                        (1R,2R,3S)-2-carbomethoxy-                                                                           0.25   mg/kg                                           3-(3,4-dichlorophenyl)-tropane                                                ______________________________________                                    

Side effect profile of the compounds of the present invention

The side effects of cocaine and the central stimulant amphetaminederivatives involve central excitement and stimulation in animalsincluding primates and these effects can also be observed in humans. Aserious side effect of cocaine and of the amphetamine derivativesincludes also the ability to provoke toxic psychotic symptoms closelyresembling the mental disease schizophrenia and these includehalucinations, paranoia and abnormal bizarre stereotyped mental activityand stereotyped motor activity.

The current knowledge strongly indicates and suggests that thesesyndromes in primates and in humans are due to an extensive and massiverelease of dopamine within the striatal complex and in particular withinthe mesolimbic dopamine system, which innervate limbic structuresincluding the nucleus accumbens.

The induction of stereotyped abnormal behavior in rodents thus alsorepresents one of the most used animal models of schizophrenia in modelsfor antipsychotic neuroleptic drugs (including haloperidol andchlorpromazine).

The development of toxic abnormal stereotyped amphetamine syndrome asdescribed below may predict a toxic central stimulant side effect ofdopamine releasing compounds in humans.

Classification of the behavioural excitatory Iocomotor and rearingresponses after amphetamine, cocaine and various dopamine uptakeinhibitors.

Male SPF wistar rats weighing 200-250 g were used for the grossbehavioural studies. All rats were transferred the day before theexperiments to individual cages made of wire netting (floor area 21×27cm, height 16 cm) at a room temperature of 21°-23° C. As a rule the ratswere observed continuously for 5-6 hrs after the administration of thedrugs. The behavioural elements here classified as rearing (i.e.standing up on the hindlegs) and Iocomotor activities (i.e. forwardrunning activities) were registered, and the maximum peak effects wereclassified according to the following rating scale:

0=non-existent or very infrequent

+=weak and infrequent

++=moderate in intensity and frequency

+++=very strong, continuous and intense

The degree of Iocomotor activity was also tested and measuredquantitatively in photocell activity cages. For the measurement of thisIocomotor activity 100 g female rats are used.

                  TABLE                                                           ______________________________________                                        Compound            Dose(i.p.) Activity                                       ______________________________________                                        (1R,2R,3S)-2-(4-Chlorophenoxy-                                                                    50 mg/kg   0                                              methyl)-3-(4-fluorophenyl)tropane                                             (1R,2R,3S)-2-carbomethoxy-                                                                        25 mg/kg   0                                              3-(2-naphthyl)-tropane                                                        (1R,2R,3S)-2-carbomethoxy-                                                                        50 mg/kg   +                                              3-(3,4-dichlorophenyl)-tropane                                                ______________________________________                                    

Classification of the abnormal stereotyped behaviour.

In general, the abnormal stereotyped behaviour after administration ofamphetamine and cocaine-like central stimulant drugs can be classifiedinto "low" and "high" intensity scores of stereotyped behaviour. The lowintensity score of stereotype includes an abnormal and continuousrepetition of the Iocomotor, rearing and sniffing behaviour, and thesesyndromes are usually seen only after the lower doses of the centraldopaminergic central stimulant drugs or may be seen present during thepre- and afterphases of the high doses. The low intensity behaviouraleffects are here included into the Iocomotor and rearing syndrome.

The high intensity syndrome of stereotype is here considered, if thebehavioural repertoire of the rat becomes strongly restricted invariation and consists of the continuous repetition of one or a fewitems of behaviour.

The syndrome of stereotyped sniffing behaviour is thus performedcontinuously on only a small restricted area of the cage. This activityusually starts on the upper part of the wall and following higher dosesof the drugs increases in intensity to the performance of sniffingtowards the lower part of the cage on the wall or on the wires of thefloor. During this stage of high intensity stereotype all normalbehavioural elements are absent including behaviour such as eating,drinking, grooming and normal explorative investigation of theenvironment. In rats, the high intensity sniffing can develop intosniffing associated with licking and/or biting-gnawing activity on thewire netting of the cage following still higher doses of the stimulantdrugs. The rats are here usually sitting in a typical crouched posturein a corner of the cage. Backward locomotion may occasionally beobserved.

The following rating scale is used for the high intensity stereotype onthe condition that the behavioural syndromes are as described above:

+=only stereotyped sniffing

++=stereotyped sniffing and episodic licking

+++=Continuous licking and/or biting gnawing

                  TABLE                                                           ______________________________________                                        Compound            Dose(i.p.) Activity                                       ______________________________________                                        (1R,2R,3S)-2-(4-Chlorophenoxy-                                                                    50 mg/kg   0                                              methyl)-3-(4-fluorophenyl)tropane                                             (1R,2R,3S)-2-carbomethoxy-                                                                        25 mg/kg   0                                              3-(2-naphthyl)-tropane                                                        (1R,2R,3S)-2-carbomethoxy-                                                                        50 mg/kg   +++                                            3-(3,4-dichlorophenyl)-tropane                                                ______________________________________                                    

Pharmaceutical Compositions

While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt or derivative thereof together with one or more pharmaceuticallyacceptable carriers therefor and, optionally, other therapeutic and/orprophylactic ingredients. The carrier(s) must be "acceptable" in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalcompositions and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, or capsules filled with thesame, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. Formulations containingten (10) milligrams of active ingredient or, more broadly, 0.1 to onehundred (100) milligrams, per tablet, are accordingly suitablerepresentative unit dosage forms.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavorings agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in admixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulation suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavoured base, usually sucroseand acacia or tragacanth; pastilles comprising the active ingredient inan inert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multidose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray this may be achieved for example bymeans of a metering atomising spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, formulations adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

Method of Treating

The compounds of this invention are extremely useful in the treatment ofdrug abuse, depression and Parkinsonism due to their potent dopamineuptake-inhibiting activity together with their low degree of undesiredside-effects. These properties make the compounds of this inventionextremely useful in the treatment of drug abuse, depression andParkinsonism as well as other disorders sensitive to the dopamineuptake-inhibiting activity of the compounds of the present invention.The compounds of this invention may accordingly be administered to aliving animal body, including a human, in need of treatment,alleviation, or elimination of an indication associated with orresponsive to dopamine uptake-inhibiting activity. This includesespecially drug abuse, depression and Parkinsonism.

Suitable dosage range are 0.1-500 milligrams daily, 10-50 milligramsdaily, and especially 10-30 milligrams daily, dependent as usual uponthe exact mode of administration, form in which administered, theindication toward which the administration is directed, the subjectinvolved and the body weight of the subject involved, and further thepreference and experience of the physician or veterinarian in charge.

The following examples will illustrate the invention further, however,they are not to be construed as limiting,

EXAMPLE 1

(-)-Anhydroecgonine methyl ester. ##STR4##

(1R,2R,3S)-2-Carbomethoxy-3-benzoxytropane, hydrochloride (100 g, 0.29mol) was refluxed in 1000 ml 1M hydrochloric acid for 18 hours and thesolution was ice cooled. Benzoic acid was collected by filtration andthe filtrate was concentrated in vacuo. Trituration of the remanescenswith ethanol and filtration yields (1R,2R,3S)-3-hydroxy-tropane 2carboxylate, hydrochloride as a white crystalline compound which withoutfurther purification was dried and refluxed in phosphorous oxychloride(50 ml) for two hours. The solution was concentrated in vacuo andabsolute methanol (150 ml) was slowly added under ice cooling. Thesolution was stirred at ambient temperature for 16 hours and wasconcentrated in vacuo. The remanescens was ice cooled and made basic byaddition of a sodium hydroxide solution (10M, approximately 100 ml) andwas extracted 5 times with diethyl ether. The combined organic phase wasdried and concentrated in vacuo yielding an oil, which was distilled invacuo (70°-74° C., 1 mBar) yielding the title compound as a clear oil.

EXAMPLE 2

(1R,2S,3S)-2-Carbomethoxy-3-(4-fluorophenyl)tropane and(1R,2R,3S)-2-carbomethoxy-3-(4-fluorophenyl)tropane ##STR5##

Grignard reagent was made in a three necked reaction flask equipped withmechanical stirring, an intensive condenser and a pressure equilibratedfunnel, using 4-bromo-fluorobenzene (27.5 ml , 250 mmol) and magnesiumturnings (6.3 g, 260 mmol) in 250 ml absolute diethyl ether. Thesolution of grignard reagent was cooled to -20° C. and a solution of(-)-anhydroecgonine methyl ester (21.7 g, 120 mmol) in 100 ml absolutediethyl ether was added over 1/2 hour. The reaction was stirred one hourat -20° C. and the reaction was quenched in one of the following twoways:

1 ) The reaction mixture was stirred into 250 ml crushed ice and thewater phase was made acidic by addition of approximately 100 ml 4Mhydrochloric acid. The organic phase was discharged and the water phasewas washed with 100 ml diethyl ether. The water phase was made basic byaddition of 25% ammonium hydroxide solution, and was then saturated withsodium chloride and was finally extracted three times with diethylether. The combined organic phase was dried and concentrated in vacuoyielding an oil which was distilled in vacuo (150°-160° C., 2 mBar).This method yields a mixture of two stereoisomers (2S/2R-1/3) which wasseparated by column chromatography using a mixture of diethyl ether andpentane (1+1)+1% triethyl amine as eluent. The crude products weretriturated in pentane yielding(1R,2S,3S)-2-carbomethoxy-3-(4-fluorophenyl)tropane, white crystals m.p.91°-92° C. and (1R,2R,3S)-2-carbomethoxy-3-(4-fluorophenyl)tropane,white crystals m.p. 65°- 66° C.

2) The reaction mixture was cooled to -78° C. and a solution oftrifluoro acetic acid (20 ml, 250 mmol) in 50 ml diethyl ether was addedover 10 minutes. The cooling bath was removed and when the temperaturehas reached 0° C. the mixture was stirred into 700 ml water. The pH ofthe water phase was adjusted to pH 1 by addition of concentratedhydrochloric acid followed by aqueous work up and purification in thesame way as described above. This method yields a mixture of twostereoisomers (2S/2R-2/1).

The following compounds were made in a similar way:

(1R,2R,3S)-2-Carbomethoxy-3-benzyltropane and(1R,2S,3S)-2-carbomethoxy-3-benzyltropane, method 2, only(1R,2S,3S)-2-carbomethoxy-3-benzyltropane was obtained withoutcontamination of the other isomer, as an oil, which crystallize uponstanding, m.p. 53°-54° C. (1R,2R,3S)-2-Carbomethoxy-3-benzyltropane wasobtained by isomerisation of the mixture as described below

(1R,2R,3S)-2-Carbomethoxy-3-(4-chlorophenyl)tropane and(1R,2S,3S)-2-carbomethoxy-3-(4-chlorophenyl)tropane, method 2, the twoisomers were not separated but the mixture was isomerized as describedbelow.

(1R,2R,3S)-2-Carbomethoxy-3-(4-chlorophenyl)tropane,(1R,2S,3S)-2-carbomethoxy-3-(4-chlorophenyl)tropane,(1S,2S,3R),2-carbomethoxy-3-(4chlorophenyl)tropane and

(1S,2R,3R)-2-carbomethoxy-3-(4-chlorophenyl)tropane, method 2, the twosets of enantiomeric pairs were not separated but the mixture wasisomerized and hydrolyzed as described below.

(1R,2R,3S)-2-Carbomethoxy-3-(4-methylphenyl)tropane and(1R,2S,3S)-2-carbomethoxy-3-(4-methylphenyl)tropane, method 2, the twoisomers were not separated but the mixture was isomerized and hydrolyzedas described below.

(1R,2S,3S)-2-Carbomethoxy-3-(2-naphthyl)tropane and

(1R,2R,3S)-2-carbomethoxy-3-(2-naphthyl)tropane, method 2, grignardreagent made by addition of a mixture of one equivalent2-bromonaphthalene and 1,2-dibromoethane in diethyl ether to a refluxingsuspension of two equivalents of magnesium. Both products were whitecrystalline compounds with m.p. 79°-80° C. C and m.p. 86°-87° C.respectively.

(1R,2R,3S)-2-Carbomethoxy-3-(1 -naphthyl)tropane and

(1R,2S,3S)-2-carbomethoxy-3-(1-naphthyl)tropane, hydrochloride, method2, grignard reagent made by addition of a mixture of one equivalent1-bromonaphthalene and 1,2-dibromoethane in diethyl ether to a refluxingsuspension of two equivalents of magnesium. The title compounds wereisolated as respectively a white crystalline compound, m.p.133°-135° C.and an amorphous compound.

(1R,2S,3S)-2-Carbomethoxy-3-(3,4-dichlorophenyl)tropane and(1R,2R,3S)-2-carbomethoxy-3-(3,4-dichlorophenyl)tropane, method 2. Bothproducts were white crystalline compounds with m.p. 69°-70° C. and61°-63° C. respectively.

(1R,2S,3S)-2-Carbomethoxy-3-(4-phenyl-phenyl)tropane and(1R,2R,3S)-2-carbomethoxy-3-(4-phenyl-phenyl)tropane, method 2. Bothproducts were white crystalline compounds with m.p. 130°-132° C. and95°-96° C. respectively.

(1R,2S,3S)-2-Carbomethoxy-3-(4-t-butyl-phenyl)tropane and(1R,2R,3S)-2-carbomethoxy-3-(4-t butyl-phenyl)tropane, method 2. Bothproducts were white crystalline compounds with m.p. 84°-85° C. and83°-84° C. respectively.

EXAMPLE 3

(1R,2R,3S)-2-Carbomethoxy-3-benzyltropane, hydrochloride. ##STR6##

To a solution of (1R,2S,3S)-2-carbomethoxy-3-benzyltropane (5.6 g, 20.5mmol) in absolute methanol (100 ml) was added a solution of sodiummethanolate in methanol (2M, 2 ml) and the mixture was refluxed for 16hours. The reaction mixture was concentrated in vacuo and theremanescens was dissolved in diethyl ether and was washed with water.The organic phase was dried and concentrated in vacuo. The crude productwas purified by column chromatography using a mixture of diethyl etherand pentane (1+1)+1% triethyl amine as eluent yielding(1R,2R,3S)-2-carbomethoxy-3-benzyltropane as an oil. By dissolution ofthis product in diethyl ether and subsequent addition of a solution ofhydrochloric acid in diethyl ether the title compound precipitates aswhite crystals, m.p. 188°-190° C.

EXAMPLE 4

(1R,2S,3S)-3-(4-Fluorophenyl)tropane 2-carboxylate, hydrochloride.##STR7##

A solution of (1R,2S,3S)-2-carbomethoxy-3-(4-fluorophenyl)tropane (5 g,18 mmol) in diluted hydrochloric acid (2M, 100 ml) was refluxed for 16hours and the reactions mixture was concentrated in vacuo. Theremanescens was triturated in ethanol and was concentrated in vacuo.Finally the crude product was triturated in cold acetone and the titlecompound was collected by filtration as white crystals, m.p.258°-260° C.

The following compound was made in a similar way:

(1R,2S,3S)-3-(2-Naphthyl)tropane 2-carboxylate, hydrochloride, yellowcrystals.

EXAMPLE 5

(1R,2R,3S)-3-Benzyltropane 2-carboxylate, hydrochloride. ##STR8##

To a solution of (1R,2R,3S)-2-carbomethoxy-3-benzyltropane (4.15 g, 15.2mmol) in ethanol (50 ml) was added an aqueous solution of sodiumhydroxide (4M, 5 ml) and the mixture was refluxed for 2 hours. Thereaction mixture was concentrated in vacuo and the remanescens wasdissolved in water and the solution was washed with diethyl ether. Theaqueous phase was acidified with concentrated hydrochloric acid and wasconcentrated in vacuo. Finally the crude product was dissolved in asmall amount of methanol and by addition of diethyl ether the titlecompound precipitates as white crystals, m.p.270°-273° C.

The following compounds were made in a similar way:

(1R,2R,3S)-3-(4-Fluorophenyl)tropane 2-carboxylate, hydrochloride, whitecrystals, m.p.>300° C.

(1R,2R,3S)-3-(4-Chlorophenyl)tropane 2-carboxylate, hydrochloride, whitecrystals, m.p. 248°-250° C.

(1R,2R,3S)-3-(4-Chlorophenyl)tropane 2-carboxylate, hydrochloride and

(1S,2S,3R)-3-(4-chlorophenyl)tropane 2-carboxylate, hydrochloride,(1+1), white crystals, m.p. 295°-297° C.

(1R,2R,3S)-3-(4-Methylphenyl)tropane 2-carboxylate, hydrochloride, whitecrystals, m.p. 264°-266° C.

(1R,2R,3S)-3-(2-Naphthyl)tropane 2-carboxylate, hydrochloride, whitecrystals, m.p. 189°-210° C. (slowly decomposing).

(1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane 2-carboxylate, hydrochloride,white crystals.

(1R,2R,3S)-3-(4-phenyl-phenyl)tropane 2-carboxylate, hydrochloride,white crystals.

(1R,2R,3S)-3-(4-t-Butyl-phenyl)tropane 2-carboxylate, hydrochloride,white crystals.

EXAMPLE 6

(1R,2R,3S)-2-(3-Methyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropane,hydrochloride. ##STR9##

To a mixture of (1R,2R,3S)-2-carbomethoxy-3-(4-fluorophenyl)tropane,methyl amide oxime (0.37 g, 5 mmol) and pulverized molecular sieves (4A,2 g) in absolute ethanol (20 ml) was added sodium (0.15 g, 6.5 mmol) andthe mixture was refluxed for 4 hours. The reaction mixture was filteredafter cooling to ambient temperature and was concentrated in vacuo. Theremanescens was dissolved in diethyl ether (30 ml) and the organic phasewas washed 3 times with water. The organic phase was dried and asolution of hydrochloric acid in diethyl ether was added to precipitatethe title compound as white crystals, m.p. approximately 100° C.,hygroscopic when heated.

EXAMPLE 7

(1R,2S,3S)-2-(3-Methyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropane,hydrochloride. ##STR10##

A solution of (1R,2S,3S)-3-(4-fluorophenyl)tropane 2-carboxylate (0.5 g,1.25 mmol) in absolute tetrahydrofurane (10 ml) was heated to reflux andcarbonyl diimidazole (0.4 g, 2.5 mmol) was added. The mixture wasrefluxed for one hour followed by addition of acetamide oxime (0.35 g,4.7 mmol) and reflux for 16 hours. After cooling of the reaction mixtureto ambient temperature, water (10 ml) was added and the mixture wasextracted with diethyl ether. The organic phase was washed three timeswith water (10 ml), dried and after evaporation of the solvent in vacuo(1R,2S,3S)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropanewas obtained as white crystals, m.p. 193°-195° C. The product wasdissolved in a small amount of diethyl ether and the title compoundprecipitates as white crystals, m.p.<100° C. (hygroscopic) by additionof a solution of hydrochloric acid in diethyl ether.

The following compounds were made in a similar way by reaction ofappropriate amide oximes with either ester or acid derivatives:

(1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-benzyltropane,hydrochloride, white crystals, m.p. 186°-187° C.

(1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane,hydrochloride, white crystals, m.p. 289°-291° C.

(1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane+(1S,2S,3R)-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane(1+1), white crystals, m.p. 108°-109° C.

(1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(4-methylphenyl)-tropane,hydrochloride, white crystals, m.p. 283°-284° C.

(1R,2S,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropane,hydrochloride, white crystals, m.p. 229°-230° C.

(1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropane,hydrochloride, white crystals, m.p. 267°-271° C.

(1R,2R,3S)-2-(3-Benzyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropane,hydrochloride, amorphous.

(1R,2R,3S)-2-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropane,hydrochloride, amorphous.

(1R,2R,3S)-2-(3-(4-Phenyl-phenyl)-1,2,4-oxadiazol-5-yl)-3-(4-fluorophenyl)tropane,white crystals, m.p. 127°-128° C.

(1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(2-naphthyl)tropane,hydrochloride, amorphous.

(1R,2R,3S)-2-(3-Methyl-1,2,4-oxadiazol-5-yl)-3-(2-naphthyl)tropane,hydrochloride, white crystals, m.p. 245°-246° C.

(1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane,hydrochloride, white amorphous substance, m.p. 60°-80° C.

(1R,2R,3S)-2-(3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)-3-(4-methylphenyl)-tropane,hydrochloride, white crystals, m.p. 273°-274° C.

(1R,2R,3S)-2-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)-3-(4-methylphenyl)-tropane,hydrochloride, white crystals, m.p. 281°-286° C.

(1R,2R,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(4-phenyl-phenyl)tropane,hydrochloride, white crystals, m.p. 307°-309° C.

(1R,2R,3S)-2-(3-Methyl-1,2,4-oxadiazol-5-yl)-3-(4-phenyl-phenyl)tropane,hydrochloride, white crystals, m.p. 259°-261 ° C.

(1R,2R,3S)-2-(3-(2-thienyl)-1,2,4ooxadiazol-5-yl)-3-(4-methylphenyl)-tropane,hydrochloride, white crystals, m.p. 276°-278° C.

(1R,2R,3S)-2-(3-Methyl-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane,hydrochloride, white crystals, m.p. 128°-130° C.

(1R,2S,3S)-2-(3-Phenyl-1,2,4-oxadiazol-5-yl)-3-(2-naphthyl)tropane,hydrochloride, amorphous.

(1R,2R,3S)-2-(3-Methyl-1,2,4-oxadiazol-5-yl)-3-benzyltropane,hydrochloride, white crystals, m.p. 179°-180° C.

(1R,2R,3S)-2-(3-(2-thienyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane,hydrochloride, white crystals, m.p. 228°-230° C.

(1R,2R,3S)-2-(3-Methyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane,hydrochloride, white crystals, m.p. 143°-145° C.

(1R,2R,3S)-2-(3-(2-Thienyl)-1,2,4-oxadiazol-5-yl)-3-(2-naphthyl)tropane,hydrochloride,white amorphous substance.

(1R,2R,3S)-2-(3-Methyl-1,2,4-oxadiazol-5-yl)-3-(4-t-butylphenyl)-tropane,hydrochloride, white crystals, m.p. 290°-291° C.

(1R,2R,3S)-2-(3-(2-Thienyl)-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane,hydrochloride, white crystals, m.p. 286°-290° C.

(1R,2R,3S)-2-(3-(4-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane,dihydrochloride, white crystals (hygroscopic), m.p. (base) 174°-184° C.

(1R,2R,3S)-2-(3-(2-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane,dihydrochloride, white crystals (hygroscopic), m.p. (base) 155°-162° C.

(1R,2R,3S)-2-(3-(4-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane,dihydrochloride, white crystals, m.p. 170°-175° C.

(1R,2R,3S)-2-(3-(3-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane,dihydrochloride, white crystals (hygroscopic).

(1R,2R,3S)-2-(3-(2-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane,dihydrochloride, white crystals (hygroscopic), m.p. (base) 163°-165° C.

EXAMPLE 8

(1R,2R,3S)-2-(3-(4-Pyridyl)-1,2,4-oxadiazol-5-yl)-3-(3,4-methylenedioxyphenyl)-tropane.##STR11##

A solution of 4-brom-1,2-methylenedioxybenzene (4 g, 20 mmol) in 25 mlabsolute tetrahydrofurane was cooled to -78° C. and n-butyllithium(2.5M, 8 ml, 20 mmol) was added over five minutes yielding a suspension.The mixture was stirred for 30 minutes and a solution of(1R)-2-(4-pyridyl)-1,2,4-oxadiazol-5-yl)-anhydroecgonine (2 g, 7.5 mmol)in 20 ml absolute tetrahydrofurane was added over 15 minutes yielding aviolet reaction mixture. After another 15 minutes stirring the reactionmixture was quenched by addition of trifluoroacetic acid (1.6 ml, 20.5mmol) and the mixture was allowed to reach room temperature. 25 ml Waterwas added and the pH was adjusted to 1 by addition of concentratedhydrochloric acid. The aqueous phase was washed twice with diethyl etherand the pH was adjusted to 10 by addition of 25% ammonium hydroxide. Thealkaline water phase was extracted twice with methylene chloride and thecombined methylene chloride phases were concentrated in vacuo yielding amixture of the (1R,2R,3S) and (1R,2S,3S) isomers. This mixture wasdissolved in 15 ml methanol and 10 ml sodium methanolate in methanol wasadded and the mixture was heated at reflux over night. The mixture wasconcentrated in vacuo and was dissolved in diethyl ether and was washed3 times with water. The ether phase was concentrated in vacuo and thecrude product was subjected to column chromatography using methylenechloride+acetone+methanol (4+1+1) as eluent. The fractions containingthe product were concentrated in vacuo and the product was recrystalizedfrom nheptane yielding the title compound as white crystals, m.p.110°-112° C.

EXAMPLE 9

(1R)-2-(4-Pyridyl)-1,2,4-oxadiazol-5-yl)-anhydroecgonine. ##STR12##

To a solution of sodium ethanolate made from sodium (4.6 g, 200 mmol)and 200 ml absolute ethanol, was added(1R,2R,3S)-2-carbomethoxy-3-benzoxytropane, hydrochloride (23.8 g, 70mmol), 4-pyridine amide oxime (30 g, 220 mmol) and molecular sieves(powder 1.5 g) and the mixture was heated at reflux over night. Water(500 ml) was added and the suspension was extracted twice withdiethylether. The ether phase was washed with water and was extractedwith 2M hydrochloric acid (150 ml). The pH of the acidic water extractwas adjusted to ten by addition of a 50% sodium hydroxide solution andthe mixture was extracted twice with diethyl ether. The ether extractswere dryed and concentrated in vacuo yielding an oil which solidifyesupon standing and was recrysttalized from water+ethanol (1+1) yieldingthe title compound as off white crystals, m.p. 104°-105° C.

EXAMPLE 10

Benzyl amide oxime. ##STR13##

To a solution of hydroxyl ammoniumchloride (38.2 g, 550 mmol) inabsolute methanol (300 ml), at room temperature, was added a methanolicsolution of sodium methanolate made by reaction of sodium (13 g, 565mmol) with absolute methanol (200 ml). The precipitate of sodiumchloride was removed by filtration and benzyl cyanide (57.7 ml, 500mmol) was added. The reaction mixture was stirred for 16 hours at roomtemperature and was then concentrated in vacuo. The remanescens wastriturated with cold methylene chloride, filtered and the crystals werewashed with ice cold methylene chloride yielding the title compound aswhite crystals, m.p. 120°-125° C.

The following compounds were made in a similar way:

4-Phenyl-phenyl amide oxime, white crystals, m.p. 177°-178° C.

Cyclopropyl amide oxime, purification by column chromatography firstusing ethyl acetate then ethyl acetate+methanol (10%) as eluent, whitecrystals, m.p. 38°-40° C.

Phenyl amide oxime, white crystals, m.p. 76°-77° C.

4-Chlorophenyl amide oxime, white crystals, m.p. 113°-115° C.

4-Fluorophenyl amide oxime, white crystals, m.p. 66°-67° C.

2-Thienyl amide oxime, white crystals, decomp. 200° C.

4-Pyridine amide oxime, white crystals.

3-Pyridine amide oxime, white crystals.

2-Pyridine amide oxime, white crystals.

EXAMPLE 11

(1R,2R,3S)-N-Normethyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)tropane,hydrochloride. ##STR14##

A mixture of(1R,2R,3S)-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)tropane(3 g, 8 mmol) and 2,2,2-trichloroethyl chloroformate (5 ml, 36 mmol) indry toluene (50 ml) was refluxed for 2 hours. The reaction mixture wasconcentrated in vacuo and to the remanescens was added methylenechloride which subsequently was washed with water. The organic phase wasdried and concentrated in vacuo. The remanescens was dissolved in 50%aqueous acetic acid (75 ml) and zinc dust (1 g) was added to thereaction mixture which thereafter was stirred at ambient temperature for16 hours. Concentrated ammonium hydroxide was added to basic reactionand the mixture was extracted twice with diethyl ether. The combinedorganic phase was dried and concentrated in vacuo and the crude reactionproduct was purified by column chromatography using methylene chloride,methanol , acetone (4+1+1) as eluent.(1R,2R,3S)-N-normethyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropanewas obtained as white crystals, m.p. 185°-187° C. which were dissolvedin a small amount of ethanol and by addition of a solution ofhydrochloric acid in diethyl ether the title compound precipitates aswhite crystals (hygroscopic), m.p.<100° C.

The following compound was made in a similar way:

(1R,2R,3S)-N-Normethyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane,hydrochloride, white crystals (hygroscopic), m.p. 100°-150° C.

EXAMPLE 12

(1R,2R,3S)-N-Normethyl-N-allyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane,hydrochloride. ##STR15##

A mixture of(1R,2R,3S)-N-normethyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane(0,29 g, 0.8 mmol), 3-bromo-1-propene (0.1 ml, 1 mmol) and potassiumcarbonate (0.14 g, 1 mmol) in absolute ethanol (25 ml) was refluxed for3 hours. The product was taken up in diethyl ether and the organic phasewas washed twice with water, dried and concentrated in vacuo. The crudeproduct was dissolved in a small amount of diethyl ether and by additionof a solution of hydrochloric acid in diethyl ether the title compoundprecipitates as white crystals, m.p. 259°-260° C.

The following compounds were made in a similar way:

(1R,2R,3S)-N-Normethyl-N-(2-hydroxyethyl)-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane,hydrochloride, white crystals, m.p. 266°-268° C.

(1R,2R,3S)-N-Normethyl-N-ethyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane,hydrochloride, white crystals, m.p. 309°-310° C.

(1R,2R,3S)-N-Normethyl-N-benzyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane,hydrochloride, white crystals, m.p. 241°-246° C.

(1R,2R,3S)-N-Normethyl-N-propargyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane,hydrochloride, off white amorphous.

(1R,2R,3S)-N-Normethyl-N-cyclopropylmethyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane,hydrochloride, white crystals, m.p. 245°-248° C.

EXAMPLE 13

(1R,2R,3S)-N-Normethyl-N-(2-acetoxyethyl)-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane,hydrochloride. ##STR16##

To a solution of(1R,2R,3S)-N-normethyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)-3-(4-chlorophenyl)-tropane(0.48 g, 1.3 mmol) in absolute dimethylformamide (4 ml) at roomtemperature was added sodium hydride (40 mg, 80%, 1.3 mmol) and themixture was stirred for 20 minutes. 2-Bromoethyl acetate (150 μl, 1.3mmol) was added and the reaction mixture was stirred over night at 70°C. After cooling to ambient temperature was ice added and the mixturewas extracted with ethyl acetate. The organic phases was concentrated invacuo and the crude product was subjected to column chromatography usingethylacetate+10% methanol as eluent. The fractions containing theproduct was concentrated in vacuo yielding an brown oil, which wasdissolved in diethyl ether and added hydrochloric acid in diethyl etherto precipate the title compound as white crystals, m.p. 245°-248° C.

EXAMPLE 14

(1R,2S,3S)-2-Hydroxymethyl-3-(4-fluorophenyl)tropane. ##STR17##

To a suspension of lithium aluminum hydride (0.8 g, 21 mmol) in diethylether (30 ml), at room temperature, was slowly added a solution of(1R,2S,3S)-2-carbomethoxy-3-(4-fluorophenyl)tropane (5 g, 18 mmol) in100 ml diethyl ether. The reaction completes after stirring for 10minutes and was quenched by addition of 0.8 ml water, 0.8 ml sodiumhydroxide (15%) and 2 ml water. The aluminum salts were removed byfiltration and the solvent was removed in vacuo leaving an oil. Thetitle compound precipitates upon trituration with pentane as whitecrystals, m.p. 79°-180° C.

The following compound was made in a similar way:

(1R,2R,3S)-2-Hydroxymethyl-3-(4-fluorophenyl)tropane, white crystals,m.p. 169°-170° C.

EXAMPLE 15

(1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(4-fluorophenyl)tropane,hydrochloride. ##STR18##

A mixture of (1R,2R,3S)-2-hydroxymethyl-3-(4-fluorophenyl)tropane (1.8g, 7.2 mmol), p-toluene-sulphonylchloride (2 g, 10.5 mmol) and triethylamine (1.6 ml, 2 mmol) in methylene chloride (50 ml) was stirred at roomtemperature for 20 hours and the reaction mixture was concentrated invacuo. Water (50 ml) and diethyl ether (50 ml) was added and the mixturewas stirred for 1/2 hour. The organic phase was washed once with sodiumhydroxide (1M), twice with water, and was then dried and concentrated invacuo. The remanescens was dissolved in a small amount of absoluteethanol and was, at room temperature, added to a solution of sodium4-chloro-phenolate in absolute ethanol, made by addition of sodium (0.24g, 10 mmol) to a solution of p-chlorophenol in absolute ethanol. Themixture was refluxed for three days and was concentrated in vacuo. Theremanescens was stirred in a mixture of water and diethyl ether and theorganic phase was washed with water. After drying and concentration invacuo, the crude product was subjected to column chromatography firstwith ethyl acetate and later with ethyl acetate and methanol (10%) aseluent. An oil was isolated which was dissolved in a small amount ofdiethyl ether and the title compound was precipitated, by addition ofhydrochloric acid in diethyl ether, as white crystals (hygroscopic),m.p. 70°-75° C.

The following compounds were made in a similar way:

(1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(3,4-dichlorophenyl)tropane,hydrochloride, white crystals (hygroscopic), m.p. 45°-50° C.

(1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(4-methylphenyl)tropane,hydrochloride, white crystals (hygroscopic), m.p. 65°-70° C.

EXAMPLE 16

(1R,2S,3S)-2-(4-Benzoyloxy-methyl)-3-(4-fluorophenyl)tropane,hydrochloride. ##STR19##

To a mixture of (1R,2S,3S)-2-hydroxymethyl-3-(4-fluorophenyl)tropane(0.5 g, 2 mmol) and potassium carbonate (0.35 g, 2.5 mmol) intetrahydrofurane (25 ml), at room temperature, was slowly added asolution of benzoyl chloride (0.3 ml, 2.5 mmol) in tetrahydrofurane (5ml). The reaction mixture was stirred for to hours at ambienttemperature and was concentrated in vacuo. Water (20 ml) was added andthe suspension was extracted twice with diethyl ether. The organic phasewas dried and was concentrated in vacuo. Thereafter the crude productwas dissolved in a small amount of diethyl ether and the title compoundwas precipitated, by addition of hydrochloric acid in diethyl ether, aswhite crystals, m.p. 230°-233° C.

The following compound was made in a similar way:

(1R,2R,3S)-2-(4-Benzoyloxy-methyl)-3-(4-fluorophenyl)tropane,hydrochloride, white crystals, m.p. 90°-91° C.

EXAMPLE 17

(1R,2R,3S)-3-(4-Fluorophenyl)tropane 2-carboxamide, hydrochloride.##STR20##

A mixture of (1R,2R,3S)-3-(4-fluorophenyl)tropane 2-carboxylate (3.4 g,12.5 mmol) and thionyl chloride (10 ml) was refluxed for one hour andthe reaction mixture was concentrated in vacuo. The remanescens was icecooled and a solution of ammonium hydroxide (25%, 20 ml) was slowlyadded. The mixture was stirred at room temperature for one hour and thewater was decanted from the formed oil. The crude product was dissolvedin a small amount of ethanol and concentrated hydrochloric acid (2 ml)was added. Addition of diethyl ether precipitates the title compoundwhich was recrystallized from isopropanol yielding white crystals, m.p.258°-260° C.

The following compound was made in a similar way:

(1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane 2-carboxamide, white crystals,m.p. 168°-170° C.

EXAMPLE 18

(1R,2R,3S)-3-(3,4-Dichlorophenyl)tropane 2-cyanide, hydrochloride, whitecrystals. ##STR21##

To an icecooled solution of triphenylphosphine (2.2 g, 8.5 mmol) in 50ml methylenechloride was added bromine (0.43 ml, 8.5 mmol) yielding asligthly brown solution. The brown color was removed by addition of asmall amount of triphenylphosphine. To the icecooled solution was added(1R,2R,3S)-3-(3,4-dichlorophenyl)tropane 2-carboxamide (2.1 g, 6.7 mmol)and triethylamine (2.4 ml, 17 mmol) and the reaction mixture was stirredfor 15 minutes. The reaction mixture was washed with water, dryed andconcentrated in vacuo. The remanescens was extracted with diethyl etherand a crude product was precipitated by addition of hydrochloric acid indiethyl ether. The crude product was recrystallized from ethanolyielding the title compound as white crystals, m.p. 268°-270° C.

EXAMPLE 19

(1R,2R,3S)-2-(4-Chlorophenoxy)carbonyl-3-(4-fluorophenyl)tropane.##STR22##

A mixture of (1R,2R,3S)-3-(4-fluorophenyl)tropane 2-carboxylate (1.4 g,5 mmol) and thionyl chloride (5 ml) was refluxed for one hour and thereaction mixture was concentrated in vacuo. The remanescens wassuspended in diethyl ether (20 ml) and a solution of 4-chlorophenol(0.64 g, 5 mmol) and triethyl amine (1.4 ml, 10 mmol) in diethyl ether(10 ml) was added at room temperature. The mixture was stirred at roomtemperature over night and tetrahydrofurane (30 ml) was added and themixture was refluxed for three hours. The reaction was quenched byaddition of water (50 ml) and was extracted with diethyl ether. Thecombined organic phase was washed with sodium hydroxide (1M) and threetimes with water. After drying and concentration in vacuo the crudeproduct was subjected to column chromatography first with ethyl acetateand later with ethyl acetate and methanol (20%) as eluent yielding thetitle compound as white crystals, m.p. 64°-66° C.

EXAMPLE 20

(1RS,2RS)-2-Carbomethoxy-3-tropanone. ##STR23##

To a suspension of sodium hydride (3.2 g 80%, 107 mmol, prewashed incyclohexane) and dimethylcarbonate (9.13 ml, 108 mmol) in absolutecyclohexane heated to reflux temperature, a solution of (±)-3-tropanone(6.9 g, 50 mmol) in 50 ml absolute cyclohexane was added over 15minutes. No hydrogen evolution was apparent so 0.2 ml methanol wasadded. The reaction mixture was stirred over night at reflux temperatureand after cooling to ambient temperature 75 ml water was carefullyadded. To the water phase was added 40 g ammonium chloride and theresulting mixture was extracted 8 times with methylene chloride. Thecombined methylene chloride organic phases were dried and concentratedin vacuo followed by column chromatography of the crude product usingmethylene chloride with increasing amounts (up to 10%) of methanol aseluent. The fractions containing the product were concentrated in vacuoand the resulting oil was subjected to kugelrohr destillation (1 mbar,120° C., yielding the title compound as orange crystals, m.p. 104°-107°C.

EXAMPLE 21

(1RS,2RS,3RS)-2-Carbomethoxy-3-hydroxy-tropane, hydrochloride. ##STR24##

To a solution of (1RS,2RS)-2-carbomethoxy-3-tropanone (17 g, 85 mmol) in750 ml methanol cooled to -35° C. was added sodium borohydride (17 g,450 mmol) and the mixture was stirred for 4 hours. The cooled solutionwas quenched by slow addition of concentrated hydrochloric acid (40 ml)and the mixture was concentrated in vacuo. Water (400 mi) was added andthe pH was adjusted to 3 by addition of concentrated hydrochloric acid.After having washed the water phase three times with diethyl ether pHwas adjusted to 11 by addition of concentrated ammonium hydroxide andthe water phase was extracted three times with methylene chloride.Concentration in vacuo yields an oil which was dissolved in ethanol andadded concentrated hydrochloric acid followed by concentration in vacuo.Freeze drying the residue yielded the title compound as an amorphousproduct.

EXAMPLE 22

(1RS)-Anhydroecgonine methyl ester. ##STR25##

A mixture of (1RS,2RS,3RS)-2-carbomethoxy-3-hydroxy-tropane,hydrochloride (0.5 g, 2.1 mmol) and thionyl chloride (0.4 ml, 5.3 mmol)was stirred at 60° C. for two hours resulting in a clear solution. Aftercooling to ambient temperature crushed ice was added and pH was adjustedto 11 by addition of concentrated ammonium hydroxide. The mixture wasextracted twice with methylene chloride and the solvent was removed invacuo yielding the title compound as an oil which was destilled, 1 mbar70°-85° C.

EXAMPLE 23

(1R,2S,3S)-2-(4'-Fluoro-benzoyl)-3-(4-fluorophenyl)tropane and(1R,2R,3S)-2-(4'-fluoro-benzoyl-3-(4-fluorophenyl)tropane. ##STR26##

Grignard reagent was made in a three necked reaction flask equipped withmechanical stirring, an intensive condenser and a pressure equilibratedfunnel, using 4-bromo-fluorobenzene (55 ml, 500 mmol) and magnesiumturnings (12.6 g, 520 mmol) in 500 ml absolute diethyl ether. Thesolution of grignard reagent was cooled to -20° C. and a solution of(-)-anhydroecgonine methyl ester (43 g, 233 mmol) in 200 ml absolutediethyl ether was added over 1/2 hour. The reaction was first stirredone hour at -20° C. and then 16 hours at room temperature and wasfinally quenched by addition of water (50 ml). The mixture was acidifiedby addition of hydrochloric acid (4M, 50 ml) and the aqueous phase waswashed twice with diethyl ether. To the aqueous phase was added ammoniumhydroxide (25%) to basic reaction and the resulting mixture was finallyextracted three times with diethyl ether. After drying and concentrationof the combined organic phase in vacuo the crude product was subjectedto column chromatography using diethyl ether+triethyl amine (5%) aseluent, yielding(1R,2S,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, whitecrystals m.p. 178°-180° C. and(1R,2R,3S)-2-(4'-fluoro-benzoyl)-3-(4-fluorophenyl)tropane, whitecrystals m.p. 124°-140° C.

EXAMPLE 24

(1R,2R,3S)-3-(3,4-Dichlorophenyl)-2-methylcyano-tropane, hydrochloride.##STR27##

A solution of (1R,2S,3S)-2-hydroxymethyl-3-(3,4-dichloro-phenyl)tropane(6.9 g, 23 mmol), triethyl amine (7 ml, 51 mmol) and p-toluenesulphonylchloride (6.4 g, 34 mmol) in 50 ml methylene chloride was stirred overnight at room temperature followed by concentration of the reactionmixture in vacuo. Water (50 ml) and diethylether (50 ml) was added andthe mixture was stirred at room temperature for 30 minutes. The etherphase was first washed once with 15 ml 1M sodium hydroxide solutionfollowed by three times water and was finally concentrated in vacuo. Theresidue was dissolved in ethanol (200 ml) and sodium cyanide (2.5 g, 51mmol) was added. The mixture was stirred at reflux temperature for twodays followed by concentration in vacuo. The residue was stirred withdiethyl ether and water and the ether phase was washed twice with waterand concentrated in vacuo. The crude product was subjected to columnchromatography using methylene chloride+acetone+methanol (4+ 1+1) aseluent and the fractions containing the product was concentrated invacuo. The product was dissolved in a small amount of methylene chlorideand a solution of hydrochloric acid in diethylether (2M) was added. Themixture was concentrated in vacuo yielding the title compound as ahydroscopic crystals.

EXAMPLE 25

(1R ,2R, 3S)-2-(3-Phenyl-1,3, 4-oxadiazoI-5-yl)-3-(4-chlorophenyl)-tropane ##STR28##

To a suspension of (1R,2R,3S)-3-(4-chlorophenyl)tropane 2-carboxylate,hydrochloride (1 g, 3.2 mmol) in 20 ml absolute tetrahydrofurane at 60°C., N,N-carbonyldiimidazole (0.65 g, 4 mmol) was added. After stirringfor 15 minutes a clear solution was obtained and benzhydrazide (0.54 g,4 mmol) was added. The reaction was stirred over night at 60° C. and wasconcentrated in vacuo. The residue was stirred with 1M sodium hydroxidesolution (10 ml) and diethyl ether (50 ml) and the ether phase wasconcentrated in vacuo. The residue was added phosphorous oxychloride (2ml) and the mixture was stirred at 60° C. for two hours. The reactionmixture was cooled on an icebath and crushed ice was added followed by a10M sodium hydroxide solution until alkaline pH. The water phase wasextracted with ethyl acetate and the organic phase was concentrated invacuo. The crude product was recrystalized from a mixture of ethanol andwater yielding the title compound as white crystals, m.p. 164°-166° C.

The following compound was made in a similar way:

(1R,2R,3S)-2-(3-Phenyl-1,3,4-oxadiazol-5-yl)-3-(3,4-dichlorophenyl)-tropane,white crystals, m.p. 173°-174° C.

We claim:
 1. A method of treating a disorder or disease of a mammal,selected from Parkinsonism, drug addiction and abuse, and depression,which disorder or disease is responsive to the inhibition of dopaminereuptake, comprising the step of administering to such a mammal in needthereof an effective amount of a 2,3-trans disubstituted tropanecompound having the formula ##STR29## any mixture thereof, or apharmaceutically-acceptable salt thereof; whereinR is hydrogen, alkyl,alkenyl, alkynyl, cycloalkylalkyl or 2-hydroxyethyl; R³ is(CH₂)_(n) CO₂R¹¹ ; COR¹¹ ; CH₂ R¹² ;wherein R¹¹ is alkyl; cycloalkyl;cycloalkylalkyl; phenyl which may be substituted one or more times withsubstituents selected from the group consisting of halogen, CF₃, CN,alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, or aryl; phenylphenyl;pyridyl which may be substituted one or more times with substituentsselected from the group consisting of halogen, CF₃, CN, alkoxy, alkyl,alkenyl, alkynyl, amino, nitro, or aryl; thienyl which may besubstituted one or more times with substituents selected from the groupconsisting of halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino,nitro, or aryl; or benzyl; n is 0 or 1; and R¹² is O-phenyl which may besubstituted one or more times with substituents selected from the groupconsisting of halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino,nitro, or aryl; or O--CO-phenyl which may be substituted one or moretimes with substituents selected from the group consisting of halogen,CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, or aryl; and R⁴is phenyl which may be substituted one or more times with substituentsselected from the group consisting of halogen, CF₃, CN, alkoxy, alkyl,alkenyl, alkynyl, amino, nitro, or aryl; 3.4-methylenedioxyphenyl;benzyl which may be substituted one or more timeswith substituents selected from the group consisting of halogen, CF₃,CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, or aryl; or naphthylwhich may be substituted one or more times with substituents selectedfrom the group consisting of halogen, CF₃, CN, alkoxy, alkyl, alkenyl,alkynyl, amino, nitro, or aryl.
 2. The method of claim 1, whereindepression or Parkinsonism is treated.
 3. The method of claim 1, whereindrug addiction and/or abuse is treated.
 4. The method of claim 3,wherein cocaine and/or amphetamine addiction and/or abuse is treated. 5.The method of claim 1, wherein the compound employed is(1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(4-fluorophenyl)tropane; or apharmaceutically-acceptable addition salt thereof.
 6. The method ofclaim 1, wherein the active ingredient is administered in the form of apharmaceutical composition thereof, in which it is present together withat least one pharmaceutically-acceptable carrier or diluent.
 7. A2,3-trans disubstituted tropane compound having the formula ##STR30##any mixture thereof, or a pharmaceutically acceptable salt thereof;whereinR is hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkyl or2-hydroxyethyl; R³ is(CH₂)_(n) CO₂ R¹¹ ; CH₂ R¹² ;wherein R¹¹ is alkyl;cycloalkyl; cycloalkylalkyl; phenyl which may be substituted one or moretimes with substituents selected from the group consisting of halogen,CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, or aryl;phenylphenyl; pyridyl which may be substituted one or more times withsubstituents selected from the group consisting of halogen, CF₃, CN,alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, or aryl; thienyl whichmay be substituted one or more times with substituents selected from thegroup consisting of halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl,amino, nitro, or aryl; or benzyl; n is 1; and R¹² is O-phenyl which maybe substituted one or more times with substituents selected from thegroup consisting of halogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl,amino, nitro, or aryl; or O--CO-phenyl which may be substituted one ormore times with substituents selected from the group consisting ofhalogen, CF₃, CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, oraryl; and R⁴ isphenyl which may be substituted one or more times withsubstituents selected from the group consisting of halogen, CF₃, CN,alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, or aryl; 3.4-methylenedioxyphenyl;benzyl which may be substituted one or more timeswith substituents selected from the group consisting of halogen, CF₃,CN, alkoxy, alkyl, alkenyl, alkynyl, amino, nitro, or aryl; or naphthylwhich may be substituted one or more times with substituents selectedfrom the group consisting of halogen, CF₃, CN, alkoxy, alkyl, alkenyl,alkynyl, amino, nitro, or aryl.
 8. A compound of claim 7 which is(1R,2R,3S)-2-(4-Chlorophenoxy-methyl)-3-(4-fluorophenyl)tropane; or apharmaceutically-acceptable addition salt thereof.
 9. A pharmaceuticalcomposition, comprising an effective amount of a compound of claim 7, ora pharmaceutically-acceptable addition salt thereof, together with atleast one pharmaceutically-acceptable carrier or diluent.